The present invention relates to a dihalo-compound which useful as an intermediate producing for retinol and the like, and a process for producing the same.
There have been known a method for producing vitamin A by a carbon-increment reaction at the side chain of xcex2-ionone (C13) (Pure and Appl. Chem. 66, 1509, (1994)) and a process of coupling C10 sulfones with C10 aldehydes, and eliminating a sulfone group (JP-B 4-3388, JP-B 5-61265 and the like). However, xcex2-ionone (C13) is very expensive and an expensive acetaldehyde derivative is required as an oxidizing agent in a step of preparing said C10 aldehyde.
According to the present invention, vitamin A can be industrially advantageously produced in a good yield using a dihalo-compound, which can be readily derived from economically available linalool or geraniol, and
The present invention provides:
1. a dihalo-compound of formula (1): 
xe2x80x83wherein
X1 and X2 represent different halogen atoms,
R represents a hydrogen atom or a protective group for a hydroxyl group, and the wavy line denoted by xe2x80x9cxe2x80x9d means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof,
2. a method for producing a dihalo-compound of formula (1) as defined above, which comprises
reacting at least one compound selected from an alcohol compound of formula (2): 
xe2x80x83an alcohol compound of formula (3): 
with a halogenating agent having a halogen atom represented by X2 as defined in connection with formula (1) above,
wherein in formulae (2) and (3) X1 represents a halogen atom, R represents a protective group for a hydroxy group, and the wavy line denoted by xe2x80x9cxe2x80x9d means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof, and
3. a method for producing a sulfone derivative of formula (5): 
xe2x80x83wherein
Ar represents an optionally substituted aryl group,
R represents a hydrogen atom or a protective group for a hydroxy group, and the wavy line denoted by xe2x80x9cxe2x80x9d means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof,
which comprises
reacting a sulfone compound of formula (6): 
wherein Ar is the same as defined above, with a dihalo-compound of formula (1): 
wherein X1 and X2 represent different halogen atoms and the wavy line denoted by xe2x80x9cxe2x80x9d means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof, in the presence of a base.
The present invention will be explained in detail below.
X1 and X2 represent different halogen atoms. Examples of a halogen atom represented by X1 or X2 in the formulae of the present invention include a chlorine atom, a bromine atom, and an iodine atom. X1 preferably represents a bromine atom, and X2 preferably represents a chlorine atom.
Examples of the protecting group for a hydroxy group represented by R include
an acyl group such as formyl, acetyl, ethoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, propionyl, 2-chloropropionyl, 3-chloropropionyl, butyryl, 2-chlorobutyryl,3-chlorobutyryl,4-chlorobutyryl, 2-methylbutyryl, 2-ethylbutyryl, valeryl, 2-methylvaleryl, 4-methylvaleryl, hexanoyl, isobutyryl, isovaleryl, or pivaloyl group,
a benzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxybenzoyl, o-acetoxybenzoyl, o-methoxybenzoyl, m-ethoxybenzoyl, p-methoxybenzoyl, p-nitrobenzoyl group or the like,
a silyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or the like,
an alkoxyalkyl group such as methoxymethyl, methoxyethoxymethyl, 1-ethoxyethyl or the like,
a tetrahydropyranyl group and the like, a benzyl group, a p-methoxybenzyl group, a t-butyl group, a trityl group, a 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group and the like.
Examples of the halogenating agent having a halogen atom represented by X2 as defined in connection with formula (1) above include
a halide of a transition metal of Group 4, a halide of sulfur and a halide of phosphorus.
Said halide of a transition metal of Group 4 include
a halide of formula (4):
M(X2)a(ORxe2x80x2)4xe2x88x92axe2x80x83xe2x80x83(4)
wherein M is a transition metal of Group 4, xe2x80x9caxe2x80x9d is an integer of 1 to 4 and Rxe2x80x2 is a straight or branched chain alkyl group having 1 to 5 carbon atoms.
Examples of the metal atom xe2x80x9cMxe2x80x9d in the halide (4) of a transition metal of Group 4 include titanium, zirconium and hafnium. In particular, a titanium is preferred among them.
Examples of the linear or branched alkyl group having a carbon number of 1 to 5 represented by Rxe2x80x2 in formula (4) include a methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl, t-butyl and n-pentyl group. Specific examples of the halide of a transition metal of Group 4 represented by formula (4) include titanium tetrachloride, titanium tetrabromide, dichlorotitanium diisopropoxide, zirconium tetrachloride, hafnium tetrachloride and the like.
Examples of the halide of sulfur is thionyl chloride and examples of the halide of phosphorus include phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
An amount of the halogenating agent to be used is usually around 0.25 to 2 moles, preferably around 0.5 to 1.1 moles per mol of the total amount of the alcohols (2) and (3).
The halide of sulfur or phosphorus is preferably used in the presence of a base. The base is not particularly limited and includes an organic amine base and inorganic bases.
Specific examples thereof include pyridine, 4-dimethylaminopyridine, 3-ethyl-4-methylpyridine, 5-ethyl-2-methylpyridine, imidazole, 2-methylimidazole, 3-methylimidazole, 2-ethyl-4-methylimidazole, DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), trimethylamine, triethylamine, dimethylethylamine, methyldiethylamine, t-butyldimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. An amount of the base to be used is usually around 1 to 2 moles per mol of the alcohols (2) or (3).
The reaction is usually conducted in an organic solvent and examples of the solvent include
an ether solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, anisole and the like,
a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, benzene, toluene, xylene and the like,
a halogenated solvent such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene, o-dichlorobenzene and the like, and
an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, hexamethylphosphoric triamide and the like.
The halide of a transition metal of Group 4 is preferably used, together with an ether solvent, and dimethoxyethane is more preferable. These may be used alone or as a mixed solvent thereof. A reaction temperature can be optionally set at a range of xe2x88x9278xc2x0 C. to a boiling point of a solvent, preferably a range of around xe2x88x9220 to 60xc2x0 C.
A dihalo-compound of formula (1), wherein X1 is a bromine atom and X2 is a chlorine atom is preferred.
After completion of the reaction, the dihalo-compound (1) can be obtained by conventional post-treatment procedures. It may be purified by extraction, washing, various chromatographies or the like, if necessary.
Next, a description will be made to the method for producing a sulfone derivative of formula (5) as defined above which method comprises reacting a sulfone compound of formula (6) as defined above, with a dihalo-compound of formula (1) in the presence of a base.
Examples of the base to be used include an alkali metal alkoxide, an alkali metal hexamethyldisilazane, a hydride of an alkali metal, an alkyl lithium, a Grignard reagent. Specific examples thereof include
sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, sodium t-butoxide,
sodium hexamethyldisilazane, potassium hexamethyldisilazane,
sodium hydride, potassium hydride,
n-butyllithium, s-butyllithium, t-butyllithium,
ethylmagnesium bromide, ethylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, iso-propylmagnesium bromide, iso-propylmagnesium chloride and the like. Preferred are the alkali metal alkoxide and the alkali metal hexamethyldisilazane.
An amount of the base to be used is usually around 1 to 5 moles, preferably around 1 to 3 moles per mol of the dihalo-compound of formula (1).
The reaction is usually conducted in an organic solvent, and examples thereof include aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, hexamethylphosphoric triamide and the like, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, n-pentane, toluene, xylene and the like, and ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, anisole, a mixture thereof and the like. Preferred are aprotic polar solvents.
The reaction temperature can be optionally set usually in a range of xe2x88x9278xc2x0 C. to a boiling point of a solvent used, depending upon the base employed.
After completion of the reaction, the sulfone derivative of formula (5) may be isolated by a usual post-treatment such as extraction, phase separation, washing or the like.
The sulfone derivative of formula (5) thus formed can be further reacted with a base, optionally followed by deprotecting or protecting to produce vitamin A derivative of formula (7): 
wherein R and the wavy line have the same meanings as defined above.
The reaction mixture which has resulted from the reaction of the sulfone compound of formula (6) with a base and contains the sulfone derivative of formula (5) may be contacted as it is, without being subjected to a post-treatment, with the base. For example, said method of contacting of the reaction mixture containing the sulfone derivative (5) with a base include one-pot process in which said contacting is carried out in the same reactor as used for producing the sulfone derivative of formula (5).
Alternatively, the sulfone derivative of formula (5) may be isolated and further reacted with a base to produce the vitamin A derivative of formula (7).
Examples of the base to be used include an alkali metal hydroxide, alkali metal hydride and an alkali metal alkoxide. Specific examples thereof include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide and the like. Preferred examples of the base to be used include said alkali metal hydroxide and alkali metal alkoxide.
An amount of the base to be used is usually around 1 to 20 moles, preferably around 5 to 15 moles per mole of the sulfone derivative of formula (5).
The reaction temperature is optionally set usually at a range of xe2x88x9240xc2x0 C. to a boiling point of a solvent used, depending upon a base used in the reaction.
Lower alcohols such as methanol, ethanol, 2-propanol, and t-butanol. may be added to accelerate the progress of the reaction. An amount of an alcohol to be added is usually around 1 to 5 moles per mol of the sulfone derivative (5).
A phase transfer catalyst also may be added in this process to accelerate the reaction.
Examples of the phase transfer catalyst to be used include a quaternary ammonium salt, a quaternary phosphonium salt, a sulfonium salt and the like substituted with at least one group selected from alkyl and aryl group of a carbon number of 1 to 24.
Specific examples of the quaternary ammonium salt include tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrapentylammonium chloride, tetrahexylammonium chloride, tetraheptylammonium chloride, tetraoctylammonium chloride, tetrahexadecylammonium chloride, tetraoctadecylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, 1-methylpyridinium chloride, 1-hexadecylpyridinium chloride, 1,4-dimethylpyridinium chloride, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrapentylammonium bromide, tetrahexylammonium bromide, tetraheptylammonium bromide, tetraoctylammonium bromide, tetrahexadecylammonium bromide, tetraoctadecylammonium bromide, benzyltrimethylammonium bromide, benzyltriethylammonium bromide, benzyltributylammonium bromide, 1-methylpyridinium bromide, 1-hexadecylpyridinium bromide, 1,4-dimethylpyridinium bromide, tetramethyl-2-butylammonium bromide, trimethylcyclopropyl ammonium bromide, tetramethylammonium iodide, tetrabutylammonium iodide, tetraoctylammonium iodide, t-butylethyldimethylammonium iodide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium iodide, octadecyltrimethylammonium iodide, benzyltrimethylammonium iodide, benzyltriethylammonium iodide, benzyltributylammonium iodide and the like.
Examples of the quaternary phosphonium salt include tributylmethylphosphonium chloride,triethylmethylphosphonium chloride, methyltriphenoxyphosphonium chloride, butyltriphenylpyosphonium chloride, tetrabutylphosphonium chloride, benzyl triphenylphosphonium chloride, hexadecyldimethylethylphosphonium chloride, tetraphenylphosphonium chloride, tributylmethylphosphonium bromide, triethylmethylphosphonium bromide, methyltriphenoxyphosphonium bromide, butyltriphenylphosphonium bromide, tetrabutylphosphonium bromide, benzyltriphenylphosphonium bromide, hexadecyltrimethylphosphonium bromide, hexadecyltributylphosphonium bromide, hexadecyldimethylethylphosphonium bromide, tetraphenylphosphonium bromide, tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methylphenoxyphosphonium iodide, butyltriphenylphosphonium iodide, tetrabutylphosphonium iodide, benzyltriphenylphosphonium iodide, hexadecyltrimethylphosphonium iodide and the like.
Examples of the sulfonium salt include dibutylmethylsulfonium chloride, trimethylsulfonium chloride, triethylsulfonium chloride, dibutylmethylsulfonium bromide, trimethylsulfonium bromide, triethylsulfonium bromide, dibutylmethylsulfonium iodide, trimethylsulfonium iodide, triethylsulfonium iodide and the like.
Among the phase transfer catalysts, the quaternary ammonium salt is particularly preferred. An amount of the phase transfer catalyst to be used is usually around 0.01 to 0.2 mole, preferably around 0.02 to 0.1 mole per mol of the dihalo-compound (1).
After the reaction, the vitamin A derivative (7) can be obtained by a conventional post-treatments such as quenching with a saturated aqueous ammonium chloride solution or the like and extraction with an organic solvent, and it may be purified by crystallization, various chromatographies or the like, if necessary.
Deprotected vitamin A derivative (7) is usually obtained in the reaction of the sulfone derivative of formula (5) having an acyl protective group with a base, and it can be protected by subjecting the compound to a protection reaction with an optional protective group, if necessary. For example, vitamin A acetate can be obtained by a conventional method such as the one using acetic anhydride and pyridine or the like.
Alternatively, vitamin A derivative (7) having other protective groups can be subjected to deprotection reaction, if necessary. For example, the silyl protective group may be removed by reacting the compound with tetra-n-butylammonium fluoride, the alkoxyalkyl or tetrahydropyranyl group may be removed by a protonic acid catalyst, and 2,2,2-trichloroethoxycarbonyl can be removed by a reductive deprotection using zinc dust and acetic acid.
Said deprotecting or introducing of the protective groups can be conducted according to the conventional methods as disclosed in xe2x80x9cProtective Groups in Organic Synthesis, Greene and Wuts, 2nd Edition (1992), John Wiley and Sons, Inc, the whole disclosure of which is incorporated herein by reference.
Alcohols (2) and (3) can be readily synthesized from linalool or geraniol as shown in the following Scheme 1 (JP-A 11-130730 and JP-A 11-236357). The sulfone compound of formula (6) can be obtained by a process as disclosed in Chemistry Letters 479, (1975). Alcohols (2) and (3) may be an E or Z geometric isomer, or a mixture thereof. 
Scheme 1